Etan Orgel

Impact on Survival and Toxicity by Duration of Weight Extremes During Treatment for Pediatric Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group

PURPOSE Previous studies regarding the influence of weight on event-free survival (EFS) and treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL) considered only weight at diagnosis. Inasmuch as weight varies substantially over treatment, we hypothesized its impact on EFS is instead determined by cumulative time spent at an extreme weight during therapy and on TRT by weight at the time of toxicity. PATIENTS AND METHODS In a cohort of 2,008 children treated for high-risk ALL in Childrens Oncology Group study CCG-1961, we determined the effect on EFS of cumulative time receiving therapy at an extreme weight (either obese or underweight) between end of induction and start of maintenance therapy. We also evaluated the association between weight category and incidence and patterns of TRT during 13,946 treatment courses. RESULTS Being obese or underweight at diagnosis and for ≥ 50% of the time between end of induction and start of maintenance therapy resulted in inferior EFS (hazard ratios, 1.43 and 2.30, respectively; global P < .001). Normalization of weight during that period resulted in mitigation of this risk comparable to never being obese or underweight. Obese or underweight status at start of each treatment course was significantly associated with specific patterns of TRT. CONCLUSION Influence of weight extremes on EFS and TRT is not set at diagnosis as previously reported but is moderated by subsequent weight status during intensive postinduction treatment phases. These observations suggest that weight is a potentially addressable risk factor to improve EFS and morbidity in pediatric ALL.

A failing medical educational model: a self-assessment by physicians at all levels of training of ability and comfort to deliver bad news.

OBJECTIVE Patient surveys consistently show physician communication remains less than ideal. While previous studies have demonstrated a lack of trainee confidence in delivering bad news, our study explores communication skills at all levels of practice and highlights potential barriers to improvement. METHODS Pediatric residents, fellows, and attendings involved in direct patient care at a major academic center participated in a voluntary questionnaire, consisting of self-assessed scales of comfort level, knowledge level, amount of training, and attitudes towards communication education. We also elicited barriers to learning and teaching as well as significant experiences. RESULTS Eligible responses (n = 253) were evenly divided between trainees and faculty. Almost half of attendings and two thirds of fellows did not feel sufficiently knowledgeable to deliver bad news. Many attendings felt disproportionately more comfortable than they felt knowledgeable. All trainees felt insufficiently knowledgeable for independent practice of this skill. Educational barriers centered on time constraints, a deemphasis, a lack of positive modeling, and minimal awareness of existing resources. Poor experiences revolved around inappropriate language and settings as well as insufficient empathy or preparedness. Positive anecdotes highlighted the importance of education and the impact of role models. CONCLUSION Independent of level of training, this study reveals a lack of self-assessed preparedness from many responsible for delivering bad news to patients and families. A significant barrier to improvement is the disproportionate level of self-assessed comfort versus knowledge level. Educational models should include both didactics to learn the skills and practice-based learning to refine the techniques.

The Links Between Insulin Resistance, Diabetes, and Cancer

The growing epidemic of obesity has resulted in a large increase in multiple related diseases. Recent evidence has strengthened the proposed synergistic relationship between obesity-related insulin resistance (IR) and/or diabetes mellitus (DM) and cancer. Within the past year, many studies have examined this relationship. Although the precise mechanisms and pathways are uncertain, it is becoming clear that hyperinsulinemia and possibly sustained hyperglycemia are important regulators of not only the development of cancer but also of treatment outcome. Further, clinical decision-making regarding the treatment of choice for DM will likely be impacted as we learn more about the non-metabolic effects of the available hyperglycemic agents. In our review, we endeavored to synthesize the recent literature and provide a concise view of the journey from macro-level clinical associations to specific mechanistic relationships being elucidated in cell lines and animal models.

Obesity is associated with residual leukemia following induction therapy for childhood B- precursor acute lymphoblastic leukemia

Obesity is associated with poorer event-free survival (EFS) in pediatric acute lymphoblastic leukemia (ALL). Persistent minimal residual disease (MRD) in the bone marrow as measured by multidimensional flow cytometry (MDF) is a key early prognostic indicator and is strongly associated with EFS. We therefore hypothesized that obesity during induction would be associated with positive end-of-induction MRD (≥0.01%). We analyzed MDF of end-induction bone marrow samples from a historical cohort of 198 children newly diagnosed with B-precursor ALL (BP-ALL) and treated with Childrens Oncology Group induction regimens. We assessed the influence of body mass index on risk for positive end-induction MRD in the bone marrow. In our cohort of BP-ALL, 30 children (15.2%) were overweight and 41 (20.7%) were obese at diagnosis. Independent of established predictors of treatment response, obesity during induction was associated with significantly greater risk for persistent MRD (odds ratio, 2.57; 95% confidence interval, 1.19 to 5.54; P = .016). Obesity and overweight were associated with poorer EFS irrespective of end-induction MRD (P = .012). Obese children with newly diagnosed BP-ALL are at increased risk for positive end-induction MRD and poorer EFS.

Association of body mass index and survival in pediatric leukemia: a meta-analysis

BACKGROUND Obesity is a worldwide epidemic in children and adolescents. Adult cohort studies have reported an association between higher body mass index (BMI) and increased leukemia-related mortality; whether a similar effect exists in childhood leukemia remains controversial. OBJECTIVE We conducted a meta-analysis to determine whether a higher BMI at diagnosis of pediatric acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) is associated with worse event-free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR). DESIGN We searched 4 electronic databases from inception through March 2015 without language restriction and included studies in pediatric ALL or AML (0-21 y of age) reporting BMI as a predictor of survival or relapse. Higher BMI, defined as obese (≥95%) or overweight/obese (≥85%), was compared with lower BMI [nonoverweight/obese (<85%)]. Summary risk estimates for EFS, OS, and CIR (ALL only) were calculated with random- or fixed-effects models according to tests for between-study heterogeneity. RESULTS Of 4690 reports identified, 107 full-text articles were evaluated, with 2 additional articles identified via review of citations; 11 articles were eligible for inclusion in this meta-analysis. In ALL, we observed poorer EFS in children with a higher BMI (RR: 1.35; 95% CI: 1.20, 1.51) than in those at a lower BMI. A higher BMI was associated with significantly increased mortality (RR: 1.31; 95% CI: 1.09, 1.58) and a statistically nonsignificant trend toward greater risk of relapse (RR: 1.17; 95% CI: 0.99, 1.38) compared with a lower BMI. In AML, a higher BMI was significantly associated with poorer EFS and OS (RR: 1.36; 95% CI: 1.16, 1.60 and RR: 1.56; 95% CI: 1.32, 1.86, respectively) than was a lower BMI. CONCLUSION Higher BMI at diagnosis is associated with poorer survival in children with pediatric ALL or AML.

Hearing loss among survivors of childhood brain tumors treated with an irradiation‐sparing approach

Intensive, irradiation‐sparing chemotherapy regimens for malignant brain tumors have improved survival and neurocognitive outcomes in very young children. Platinum compounds are pivotal to this approachs success but are associated with hearing loss that markedly reduces quality of life for survivors. The purpose of this study was to determine the prevalence and severity of ototoxicity associated with Head Start and similar irradiation‐sparing regimens.

Clinical and microbiologic outcomes of quinolone prophylaxis in children with acute myeloid leukemia.

Background: Intensifying treatment for pediatric acute myeloid leukemia (AML) has improved survival, with infections now being a leading cause of morbidity. Because quinolone prophylaxis is effective in adults with AML and in transplant populations, ciprofloxacin prophylaxis (CPx) was introduced as the standard for pediatric AML. We report here the impact of CPx in this population. Methods: Prevalence of fever and neutropenia, frequency and pathogen spectrum of infections, antibiotic use, supportive care and mortality before and after implementation of CPx were retrospectively compared in children with AML. Results: The cohort included 35 patients with de novo and 10 with relapsed AML, who together underwent 153 chemotherapy courses. Fever and neutropenia resulting in the use of empiric antibiotics occurred in 90% of chemotherapy courses (137/153); this was associated with proven bacteremia in 26%. The use of CPx did not change the incidence of febrile or infectious episodes, number of days of fever or antibiotic treatment or mortality. CPx was associated with a significant decrease in infections caused by Gram-negative rods (13.4% vs 4.7%) but a concomitant significant increase in bacteremia caused by viridans streptococci (12% vs 28%), resulting in no significant overall difference in the incidence of bacteremia between the 2 groups (35.9% vs 31.5%). Conclusions: CPx neither alter the incidence of overall bacteremia nor change the pattern of fever or use of supportive care. Our experience supports further investigation into the use of extended-spectrum quinolone prophylaxis during therapy for pediatric AML.

Early cardiac outcomes following contemporary treatment for childhood acute myeloid leukemia: A north American perspective

Anthracycline agents are used for treatment of acute myeloid leukemia (AML) but may cause late‐onset cardiomyopathy. Current frontline therapy for AML in North America, as reflected in the approach of the Childrens Oncology Group (COG) and other pediatric consortia, is adapted from the anthracyline‐intensive Medical Research Council (MRC) regimen. The purpose of this study was to describe early post‐treatment cardiac function as a potential indicator of acute and long‐term risk associated with this approach.

Why Healthcare Providers Should Focus on the Fertility of AYA Cancer Survivors: It’s Not Too Late!

Reproductive health among cancer survivors is an important quality of life issue. Certain cancer therapies have known fertility risks. There is an existing cohort of adolescents and young adults (AYA) cancer survivors that, seen less frequently in clinical care settings than active patients, are likely not having discussions of fertility and other reproductive health issues. A survivor or healthcare provider can easily assume that the window of opportunity for fertility preservation has passed, however emerging research has shown this may not be the case. Recent data demonstrates a close relationship between fertility and other late effects to conclude that ongoing assessment during survivorship is warranted. Some fertility preservation procedures have also been shown to mitigate common late effects. This review explores the link between late effects from treatment and common comorbidities from infertility, which may exacerbate these late effects. This review also highlights the relevance of fertility discussions in the AYA survivorship population.

Limitations of body mass index to assess body composition due to sarcopenic obesity during leukemia therapy.

Abstract Obesity as defined by body mass index percentile (BMI%) is strongly associated with relapse and poorer survival in childhood ALL. Whether BMI% accurately reflects body fat percentage (BF%) in this population is unknown. We conducted a prospective study assessing body composition during frontline ALL therapy. Dual-energy X-ray absorptiometry measured BF% and lean muscle mass (LMM) at diagnosis, end of Induction, and end of Delayed Intensification. Sarcopenic obesity (gain in BF% with loss of LMM) was surprisingly common during ALL treatment, resulting in poor correlation between changes in BMI% (expressed as Z-score) and BF% overall (r = −0.05) and within patients (r = −0.09). BMI Z-score and BF% changed in opposite directions in >50% of interval assessments. While BMI% at diagnosis is a suitable predictor of obesity/BF% for epidemiological studies, change in BMI% (as expressed as Z-score) does not reflect body composition. Studies evaluating obesity in leukemia should consider using direct measures of body composition.